Project Summary: HIV-1 infects CD4 T cells and causes T cell depletion and immunodeficiency. Molecular interactions between the virus and T cells that occur at the early time are critical for viral infection and pathogenesis. Our preliminary studies have identified cofilin as one of the early signaling molecules targeted by the virus in order to establish latent infection of CD4 T cells. We have demonstrated that HIV-1 utilizes the viral envelope/CXCR4 signaling to activate cofilin in order to overcome the cortical actin restriction in resting CD4 T cells. This molecular event is necessary for viral nuclear migration in resting T cells. Our long-term goal is to study the molecular details of viral-host interaction that lead to aberrant signaling and cofilin activation. The specific aims of this proposal are to study the interactions between the viral envelope, gp120, and its chemokine coreceptor, CXCR4, that lead to cofilin activation. We will identify the signaling domains on gp120, as well as map the signaling pathways involved. This proposed research is significant because the information will help to identify specific cellular mechanisms hijacked by the virus to facilitate infection. These mechanisms are highly relevant to viral pathogenesis in CD4 T cells. Results from the proposed study may also identify novel therapeutic targets to inhibit viral infection.